Schizophrenia is associated with considerable morbidity and economic burdens. Knowledge about its pathophysiology is still incomplete. Some evidence exists that the brain's dorsolateral prefrontal cortex (DLPFC) may be dysfunctional in schizophrenia. Neuroimaging studies have reported both hypoactive and hyperactive DLPFC in subjects with schizophrenia involved in a cognitive task. These apparent contradictions may be due in part to the subjects' skill, performance and the difficulty of each task. Transcranial Magnetic Stimulation (TMS) is a non-invasive technique that employs a high magnetic field to activate neuron and a direct method of brain stimulation that does not depend on subject's compliance or effort. Our group at MUSC has pioneered the interleaved TMS/fMRI technology to get real-time images of brain activity with TMS. Here, we plan to use interleaved TMS/fMRI in schizophrenia subjects to investigate if DLPFC is truly hypoactive and characterize the Blood Oxygen Level Dependent (BOLD) response to TMS. We hypothesize that in subjects with schizophrenia and prominent negative symptoms (such amotivation and flat affect) will show a weaker rCBF response underneath the TMS coil as compared to matched healthy controls. Specific Methods: In this 3 year grant proposal, we plan enroll 15 schizophrenia males with prominent negative symptoms and neuroleptic free (for at least 2 weeks) and 15 healthy controls matched for age, handedness, parental education and smoking habits. They will be rated for psychosis, mood, extrapyramidal symptoms and cognition. They will undergo a high resolution structural scan to determine the location of left middle frontal gyrus (Brodmann Area 9) and to measure the distance ratio from skull to prefrontal cortex over skull to motor cortex. On a different day, they will undergo an interleaved TMS/fMRI session. We will stimulate intermittently over the left middle frontal gyrus at 1Hz and acquire 'in-the-moment BOLD fMRI scans. Each 21-second epoch of TMS will be preceded and followed by an equal length of no stimulation. TMS will be randomly delivered at 80%, 100% and 120% of motor threshold (intensity necessary to move the thumb). The intensity used will be adjusted relative to the degree of prefrontal atrophy if needed. Changes in rCBF will be the primary outcome measures. Conclusions: This study builds on the Prs preliminary work with interleaved prefrontal TMS/fMRI in healthy subjects and in one case of schizophrenia, as well as TMS research in negative [unreadable] symptoms of schizophrenia. It will assess whether TMS/fMRI is a feasible and safe method in this population. It will characterize the BOLD response to TMS (which is hypothesized to be weaker in schizophrenia subjects compared to controls). This is a necessary first step to better understand neuronal response to non-invasive stimulation in subjects with schizophrenia. In future work, results from this R2I grant will help investigating the functional connectivity of the DLPFC, the relation of TMS to complex cognitive and pharmacological probes and possibly add to the understanding of how to restore DLPFC function in patients with schizophrenia. [unreadable] [unreadable]